Cortical Gray and White Matter Volume in UnmedicatedSchizotypal and Schizophrenia Patients

Erin A. Hazlett1,*, Monte S. Buchsbaum1, M. Mehmet Haznedar1, Randall Newmark1, Kim E.Goldstein1, Yuliya Zelmanova1, Cathryn F. Glanton1, Yuliya Torosjan1, Antonia S. New1,2,Jennifer N. Lo1, Vivian Mitropoulou1, and Larry J. Siever1,2

1Department of Psychiatry, Mount Sinai School of Medicine, New York, NY

2Bronx Veterans Affairs Medical Center, NY and Mental Illness Research, Education and Clinical Center(MIRECC) and VISN 3

AbstractMagnetic resonance (MR) imaging studies have revealed fronto-temporal cortical gray mattervolume reductions in schizophrenia. However, whether age- and sex-matched unmedicatedschizotypal personality disorder (SPD) patients share some or all of the structural brain-imagingcharacteristics of schizophrenia patients has not been studied. We examined cortical gray/whitematter volumes in a large sample of unmedicated schizophrenia-spectrum patients (n=79 SPD, n=57schizophrenia) and 148 healthy controls. MR images were reoriented to standard position parallel tothe anterior-posterior commissure line, segmented into gray and white matter tissue types, andassigned to Brodmann areas (BAs) using a postmortem-histological atlas. Group differences inregional volume of gray and white matter in the BAs was examined with MANOVA. Schizophreniapatients had reduced gray matter volume widely across the cortex but more marked in frontal andtemporal lobes. SPD patients had reductions in the same regions but only about half that observedin schizophrenia and sparing in key regions including BA10. In schizophrenia, greater fronto-temporal volume loss was associated with greater negative symptom severity and in SPD, greaterinterpersonal and cognitive impairment. Overall, our findings suggest that increased prefrontalvolume in BA10 and sparing of volume loss in temporal cortex (BAs 22 and 20) may be a protectivefactor in SPD which reduces vulnerability to psychosis.

KeywordsMRI; schizophrenia; schizotypal personality disorder; frontal lobe volume; temporal lobe volume;cingulate gyrus; negative symptoms; gray matter volume; white matter volume

1. IntroductionNumerous studies have reported structural brain imaging abnormalities in schizophrenia-spectrum disorders. Similar to schizophrenia, cerebrospinal fluid (CSF) is increased andcortical volumes are decreased in schizotypal personality disorder (SPD) (Buchsbaum et al

*Corresponding author: Erin A. Hazlett, Ph.D, Department of Psychiatry, Box 1505, Mount Sinai School of Medicine, New York, NY10029, Email: E-mail: erin.hazlett@mssm.edu, Phone: (212) 241-2779.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain.

NIH Public AccessAuthor ManuscriptSchizophr Res. Author manuscript; available in PMC 2009 April 23.

Published in final edited form as:Schizophr Res. 2008 April ; 101(1-3): 111–123. doi:10.1016/j.schres.2007.12.472.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

1997; Dickey et al 2000; Koo et al 2006). Temporal cortex volume reductions, particularly inthe superior temporal gyrus (STG) have been consistently reported in schizophrenia (Davidsonand Heinrichs 2003; Downhill et al 2001; Gur et al 2000; Hirayasu et al 2000; Shenton et al2001; Wright et al 2000). Reduced temporal cortex volume has also been observed in SPD inSTG (Dickey et al 1999; Kawasaki et al 2004; Takahashi et al 2006a), Heschl’s gyrus (Dickeyet al 2002b), and middle and inferior temporal gyrus (Downhill et al 2001) in some but not allstudies (Takahashi et al 2006b). Studies with schizophrenia patients and their relatives alsosuggest reduced medial temporal volume including the amygdala and/or hippocampalcomplex, but these findings have not been consistently observed in SPD (Dickey et al 2002a;Dickey et al 1999; Seidman et al 2002; Seidman et al 2003). One recent study reported reducedhippocampal volume in SPD (Dickey et al 2007). Taken together, these findings are consistentwith a model of common temporal lobe abnormalities across the schizophrenia spectrum.

While SPD and schizophrenia patients appear to show some common temporal lobeabnormalities, SPD patients do not appear to show volumetric decreases in frontal cortex tothe same extent as schizophrenia (Kawasaki et al 2004; Siever et al 1990; Siever and Davis2004; Siever et al 2002; Suzuki et al 2005). Reductions in frontal volume are associated withthe deficit-like symptoms of SPD, implying that patients with smaller frontal lobe volume aremore likely to display traits such as asociality (Diwadkar et al 2006; Raine et al 1992; Sieveret al 1993). We (Haznedar et al 2004) and others (Takahashi et al 2004) have reported thatcingulate gray matter volume is relatively preserved in SPD compared with schizophrenia.Volume reductions in the parietal lobe have also been reported to show a spectrum pattern withmore widespread gray matter reductions in schizophrenia than SPD (Zhou et al 2007). Althoughrelatively fewer anatomical MRI studies have been conducted in SPD, they suggest that SPDpatients show abnormalities in some, but not all of the brain regions implicated inschizophrenia.

Individuals with SPD share a broad range of similarities with schizophrenia patients in termsof genetics, neurobiology, and phenomenology (Siever and Davis 2004). These similaritiesmay be essential for the pathogenesis of schizophrenia and related to the vulnerability toschizophrenia. However, additional pathological changes may be required for the developmentof overt and sustained psychosis. Siever and Davis (Siever and Davis 2004) suggest a modelof schizophrenia-spectrum disorders which hypothesizes that shared deficits may reflect acommon neurodevelopmentally based cortical pathology (e.g., temporal cortex). However, incontrast to patients with schizophrenia, SPD patients are hypothesized to have reducedvulnerability to psychosis due to protective factors which include greater prefrontal reserves.Factors such as capacity to recruit alternate prefrontal areas (e.g., BA10) to compensate forother dysfunctional areas during cognitive demands (Buchsbaum et al 2002) and less reducedfrontal lobe volume when compared to schizophrenia (Suzuki et al 2005) may protect the SPDpatients from chronic schizophrenia (Siever and Davis 2004).

Prior MRI work comparing SPD and schizophrenia patients, e.g., (Kawasaki et al 2004; Zhouet al 2007) has involved medicated patients or voxel-based morphometry which did not providecombined three-group contrasts, a comparison of the magnitude of volume change in SPD andschizophrenia, or statistical contrasts of different BAs or hemispheric differences. The maingoal of this study was to use MRI to determine the extent to which cortical gray and whitematter volume differs from normal in a large, unmedicated schizophrenia-spectrum sample.We examined gray and white matter volume within BAs of the entire cortex and the cingulategyrus in three age- and sex-matched groups: healthy controls and unmedicated patients withSPD or schizophrenia. We hypothesized that there would be a distinction between schizotypyand schizophrenia in terms of underlying regional cortical volume; SPD patients would showless severe prefrontal and temporal cortex volume reductions than schizophrenia patients. Wealso explored the symptomatic correlates of fronto-temporal cortex volume in our large sample

Hazlett et al. Page 2

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

and hypothesized that in both groups, fronto-temporal volume reductions would be associatedwith greater symptom severity.

2. Method2.1. Participants

We studied three age- and sex-matched groups: 79 individuals with schizotypal personalitydisorder, 57 patients with schizophrenia, and 148 healthy controls. The three groups did notsignificantly differ in age or sex. Demographic and clinical data are presented in Table-1.

All patients met DSM-IV criteria and were off medication at the time of their MRI scans fora minimum of two weeks. All participants were screened for severe medical or neurologicalillness and head injury by comprehensive medical history, and laboratory tests taken by aphysician. Healthy controls and SPD patients received an interview with a psychologist usingthe Structured Clinical Interview for DSM-III-R Axis I disorders (Spitzer et al 1992) and theStructured Interview for DSM-III-R Personality Disorders (Pfohl et al 1989). Schizophreniapatients were diagnosed using the Comprehensive Assessment for Symptoms and History(Andreasen et al 1992). Participants were excluded if they met lifetime criteria for substancedependence or abuse in the past six months, had taken any psychotropic medications in the lasttwo weeks, or had a positive urine toxicology screen for drugs of abuse. Healthy controls hadno personal history, nor a first degree relative with an Axis I or Axis II diagnosis.

The healthy controls and majority of the SPD patients (90%) were recruited throughadvertisement in local newspapers. The remaining SPD patients were recruited throughreferrals from psychiatric clinics at the Bronx Veterans Affairs Medical Center and MountSinai. Schizophrenia patients were recruited from inpatient and outpatient units at both of thesehospitals. Participants provided written informed consent in accordance with InstitutionalReview Board guidelines. A subgroup of the healthy controls (n=24), SPD patients (n=12),and schizophrenia patients (n=26) were previously included in studies examining Brodmannareas using FDG-PET (Buchsbaum et al 2002), cingulate volume (Haznedar et al 2004) andwhole temporal lobe volume (Downhill et al 2001).

All of the schizophrenia patients received the Brief Psychiatric Scale (BPRS) (Overall andGorham 1962) within one week of their MRI scan. We report the total 18-item BPRS score,Positive and Negative Symptom Factor scores (Opler 1984). Since BPRS was not obtained forthe SPD patients, we grouped their DSM symptoms into three composite scores: interpersonal,paranoid, and cognitive/perceptual based on our prior work (Bergman et al 1996; Mitropoulouet al 2002). These factors have been argued to be more sensitive than the BPRS in SPD patientsand the interpersonal factor resembles the negative symptom score on the BPRS.

2.2 MR image collectionT1-weighted axial MRI scans were acquired with a 1.5-T Signa-5x system. The acquisitionparameters were: repetition time=24 msec, echo time=5 msec, flip angle=40°, slicethickness=1.2 mm, pixel matrix=256×256, field of view=23 cm, and total slices=128. MRIscans were re-sectioned to standard Talairach-Tournoux (Talairach and Tournoux 1988)position.

2.3 Brodmann area measurement and tissue type quantificationGray and white matter volumes within Brodmann areas and cingulate gyrus were analyzed oncoronal MRI slices using our standard methods briefly described below and detailed elsewhere(Buchsbaum et al 2002; Hazlett et al 1998; Mitelman et al 2005a).

Hazlett et al. Page 3

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

A digitized version of a histologically-based atlas (Perry et al 1991) which includes 33 coronalslice maps of Brodmann areas defined by microscopic examination of one entire postmortembrain was used to delineate the Brodmann areas. Coronal slices perpendicular to the anterior-posterior commissure line were reconstructed in a 256×256 pixel matrix. First, we determinedthe front (first slice containing the cortical ribbon) and back of the brain (last slice containingthe cortical ribbon) and identified 33 evenly spaced slices such that the first slice began 1/34thof the distance from front to back. For each temporal lobe, we identified the slice with theanterior temporal pole and the most posterior extent of the Sylvian fissure and divided theinterval into 13 equally spaced slices. The posterior extent was determined by following themain fissure posteriorly until it had no sulcal depth. The brain edge was obtained on theapproximately circular 33 non-temporal slices and 26 (13 in each hemisphere) temporal slicesby depositing points visually on the tips of the gyri and then fitting a spline curve to the points.Each slice was then divided into 20 radial sectors on each hemisphere surface and 10 midlinesectors. Brodmann areas were then assessed for the gray matter, white matter, and CSF pixelswithin each sector (see later discussion of segmentation method); means were weightedaccording to the number of sectors in each region of interest and proportionally combined toobtain a single measure. Four Brodmann areas were combined (1-2-3-5) as delineated by Perry.

For gray matter and white matter quantification, the coronal images for each of the lobes weresegmented into matter type by using cut-off values individually determined in each subject byexamining the within-brain-edge histogram of axial MRI signal intensity values. Every subjecthad a clear point of rarity between gray and white matter. Validation of our gray/white mattersegmentation approach has been reported (Mitelman et al 2003; Mitelman et al 2005a).

2.4 Statistical methodsWe obtained volume data from 39 Brodmann areas (BAs: 1-2-3-5, 4,6,7a, 7b,8,9,10,11,12,17,18,19,20,21,22,23,24,25,27,28,29,30,31,32,34,35,36,37,38,39,40,41,42,43,44,45,46, and 47) identified by the Perry atlas (Figure-1). Subgroups of these variablesdeveloped on a theoretical and anatomical basis were entered into a series of mixed-designMANOVAs with diagnostic group (Healthy controls vs. SPD vs. Schizophrenia) as thebetween-group factor. Repeated measures included: region (e.g., orbital, dorsolateral), selectedsets of Brodmann areas (nested within regions, e.g., orbital: BA11, BA12, BA47 anddorsolateral: BA44, BA45, BA46), hemisphere, and tissue type (gray, white matter).Group×Region and higher order interactions were examined to establish regional differences.Follow-up simple interactions were performed to identify the strongest sources of groupinteractions. We computed relative size as the ratio of area of ROI volume/total brain volumemultiplied by 100. While ratio measures may not adequately correct for normal variation inintracranial volume, they are more commonly reported. Note that in reporting repeated-measures MANOVA, means for the main effect of diagnostic group and Group×Regioninteractions are collapsed across the BAs.

For the multivariate analysis of variance (MANOVA), we report the multivariate (Wilkslambda) F from Statistica (StatSoft 2003). Fisher’s Least Significant Differences (LSD) testswere used to follow-up significant interaction effects with diagnostic group. We examine onlythe frontal lobe, cingulate, and lateral temporal lobe with nested MANOVA. This approach,which provided tests of hypothesized group differences, helps minimize Type I statistical errorinvolved with t-tests for each area, group contrast, and hemisphere. In a further effort, we onlyexamine significant main effects for diagnostic group and interactions between diagnosticgroup and gray/white and hemisphere or within-region Brodmann area effects. To examinesymptom correlates of gray/white matter volume in prefrontal and temporal cortex, we usedPearson product-moment correlations. Lastly, because some studies have identified additional

Hazlett et al. Page 4

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

brain regions-of-interest, we report exploratory t-tests on every Brodmann area as asupplementary table only.

3. ResultsWe present the mean volumes and standard deviations for each of the Brodmann areas by groupin a supplementary table (Table-2). Our hypothesis-driven MANOVA results are presentedbelow.

3.1 Cingulate gyrus arch volumeA Group×Cingulate Brodmann area (BA25,24,31,23,29)×Matter type×HemisphereMANOVA examined whether there were schizophrenia-spectrum differences in cingulategyrus volume. Compared with healthy controls, both SPD and schizophrenia patients hadsignificantly less gray matter volume (mean±SD: healthy controls=0.226± 0.024, SPD=0.215±0.018, schizophrenia=0.218±0.023), SPDs had significantly greater white matter volume andthe two patient groups did not differ from each other (healthy controls=0.226±0.024,SPD=0.233±0.018, schizophrenia=0.230±0.023; Significant Group × Matter type interaction(F[2,281]=7.44, p=0.0007, Wilks; significant post-hoc comparisons were p<0.002).

Compared with healthy controls, the schizophrenia patients displayed the greatest reduction incingulate volume in BA24 and SPD patients were intermediate, although none of the follow-up tests reached significance (Figure-2). The gray/white matter effect was largest for BA24,31, and 23 (Figure-3). Follow-up tests revealed that both patient groups had significantly lessgray and more white matter in BA31. SPD patients also showed reduced gray but increasedwhite matter in BA24 and BA23 (all p<0.04, LSD). Schizophrenia patients had significantlyreduced gray matter in BA31. White matter volume in BA24 was significantly greater in SPDthan schizophrenia patients and this was the only cingulate region where the patient groupsdiffered (p=0.002, LSD). The main effect of group (p=0.46) and none of the other interactionswith group reached significance.

3.2 Anterior, orbital, and dorsolateral prefrontal cortex volumeA Group×Rregion (Anterior: BA 8,9,10; Orbital: BA 11,12,47; Dorsolateral: BA 44,45,46)×Brodmann area×Matter type×Hemisphere MANOVA examined whether schizophrenia-spectrum differences existed within prefrontal cortex. The schizophrenia patients hadsignificantly reduced overall gray (p=0.000013) but not white matter volume in prefrontalcortex (averaged across hemisphere and all BAs) compared with the controls and SPD patients(Figure-4). Compared with healthy controls, schizophrenia patients had reduced volume in theanterior region of the prefrontal cortex, especially BA10, (p=0.003, LSD test) while SPDpatients showed greater-than-normal BA10 volume (Figure-5). In the right hemisphere, bothpatient groups showed reduced prefrontal volume while in the left hemisphere, schizophreniabut not SPD patients showed reduced volume, predominantly in the anterior prefrontal region(BA8, 9, and 10; Group×Region×Hemisphere interaction, F[4,560]=5.41, p=.0003,Group×Hemisphere interaction, F[2,281]=3.96, p=.02). Neither the main effect of group(p=0.15), nor any of the other interactions with group were significant.

3.3 Temporal lobe (BA22, 21, and 20) volumeA Group×Region(superior: BA22, middle: BA21, and inferior temporal gyrus: BA20)×Mattertype×Hemisphere MANOVA was conducted to examine group differences in the temporalcortex. There was a highly significant main effect of group which indicated a spectrum patternwith Healthy controls>SPD>Schizophrenia patients for average relative temporal lobe volume(F[2,281]=5.14, p=0.006; Controls: mean=0.659±0.042, SPD patients: mean=0.649±0.044,Schizophrenia patients: mean=0.638±0.048). This spectrum pattern was found in the left

Hazlett et al. Page 5

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

hemisphere but in the right hemisphere, the schizophrenia patients showed reduced volumeand the SPD patients were similar to normal (Group×Hemisphere interaction, F[2,281]=10.60,p=0.00004). A Group×Matter type interaction indicated a spectrum pattern for temporal lobegray matter with C>SPD>Sz and the opposite Sz>SPD>C for white matter (F[2,281]=12.67,p=0.000005). Compared with controls, both patient groups showed reduced gray mattervolume in the middle temporal gyrus, only the schizophrenia patients showed reduced graymatter volume in superior and inferior temporal gyrus, and SPD patients showed increasedwhite matter volume in the inferior temporal gyrus (Figure-6-top).

In the superior temporal gyrus, the schizophrenia patients (p=0.03, LSD test) but not the SPDpatients showed significantly reduced volume in the left hemisphere compared to normal. Inthe middle temporal gyrus, both patient groups showed significantly reduced left (bothp<0.013) but not right volume. In the inferior temporal gyrus there were no group differencesin laterality (Figure-6-bottom).

3.4 Absolute brain volumeThe three groups did not differ on total brain volume (Controls: mean=1216cm3±SD=125;SPD patients: mean =1205cm3±125, schizophrenia patients: mean= 1214cm3±100, F[2,281]=0.20, p=0.82). Total brain volume was determined by adding the volume of gray and whitematter for all Brodmann regions across the 33 coronal slices.

In order to examine whether the three groups differed in absolute volume for the four lobes,we conducted a Group×Lobe (frontal, parietal, temporal, occipital)×Matter type×HemisphereMANOVA. Brodmann areas included for each lobe were as follows: frontal lobe:BA8,9,10,11,12,32,44,45,46, and 47; parietal lobe: BA7,39, and 40; temporal lobe:BA20,21,22,27,28,30,35,36,37,38,41, and 42; and occipital lobe: BA17,18, and 19. The groupsdid not differ in overall absolute volume (collapsed across all lobes, matter type, andhemisphere), F[2, 281]=1.27, p=0.28. Compared with the healthy controls, the schizophreniapatients showed significantly reduced gray matter volume in all four lobes, however, thetemporal lobe reduction (p<0.004, LSD test) was most striking and more prominent in the lefthemisphere (Group×Lobe interaction (F[6,558]=2,41, p=0.026; Group×Lobe×Hemisphereinteraction, F[6,558]=2.49, p=0.02). Schizophrenia patients showed small increases in whitematter in all four lobes compared with healthy controls. In contrast, SPD patients showed moremild gray matter reductions in frontal, parietal, and temporal cortex, and none in occipitalcortex (Group×Lobe×Matter type interaction, F[6,558]=4.12, p<0.0005; Figure-7). TheGroup×Matter type interaction confirmed a spectrum pattern showing controls had greateroverall gray matter volume averaged across the four lobes, schizophrenia patients had the least,and SPD patients were intermediate, while the pattern was reversed for white matter volumewith schizophrenia patients having the greatest white matter volume (F[2,281]=9.74,p=0.00008). A Group×Hemisphere interaction indicated that overall volume shrinkage wasmarked in both the left and right hemispheres in schizophrenia while SPD patients wereintermediate between healthy controls and schizophrenia patients in the left hemisphere, butsimilar to normal in the right (F[2,281]=8.37, p<0.0003). A MANOVA on relative volume forthe four lobes produced the same pattern of significant group differences (e.g.,Group×Lobe×Matter type interaction, F[6,558]=4.20, p<0.0004).

3.5 Symptom correlatesTo minimize the number of tests, we conducted volume vs. clinical symptom correlations withonly the seven BAs in prefrontal and temporal cortex where we found significant between-group volume differences (i.e. significant interactions with Group: BA24, 8, 9, 10, 22, 21, and20).

Hazlett et al. Page 6

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Among the schizophrenia patients, smaller gray and larger white matter volume in fronto-temporal BAs was associated with greater severity of BPRS negative symptoms (Table-3). Incontrast, individual differences in positive symptom severity was generally not associated withcortical volume.

Only two of the seven BAs examined showed significant correlations in the SPD group. Smallergray matter volume in BA24 was associated with greater interpersonal impairment (r=−0.31,p=.007). Smaller white matter volume in BA22 (STG) was associated with greater cognitiveimpairment (r=−0.25, p=.026).

4. DiscussionThe present study indicates the schizophrenia patients had reduced gray matter volume widelyacross the cortex but more profoundly in the frontal and temporal lobes. The SPD patientssimilarly had reduced volume in the frontal and temporal lobes only and the decrease was abouthalf that observed in schizophrenia. Thus, for the frontotemporal deficit, the schizophrenia-spectrum concept is supported with SPD patients intermediate between healthy controls andschizophrenia patients. This spectrum finding suggests that SPD probably represents a milderform of disease along the schizophrenia continuum which is consistent with the review ofDickey et al. (Dickey et al 2002a) and other morphometric studies involving SPD andschizophrenia patients (Kawasaki et al 2004; Suzuki et al 2005; Takahashi et al 2006b).

However, detailed analyses of each Brodmann area have suggested additional possiblevariations (Buchsbaum et al 2002). Four potential possibilities of normal-SPD-schizophreniadifferences may be evaluated: a spectrum for the brain region with SPD intermediate betweennormal and schizophrenia, a sparing of the region with SPD the same as normal, a protectivefactor with SPD larger than normal, and a commonality with SPD and schizophrenia showingidentical values. The whole prefrontal cortex, anterior cingulate (BA24) and left temporal lobe(BA21) are all examples of this spectrum relationship. Left temporal lobe BA22 shows verymuch smaller-than-normal volumes in schizophrenia patients than SPD patients, indicating thesparing pattern. Polar frontal lobe, BA10 is an example of a possibly protective orcompensatory area with total volume (averaged over gray and white matter) decreases inschizophrenia and increases in SPD patients. Yet, the middle temporal gyrus (BA21) andposterior cingulate (BA31) are areas where common gray matter deficits in SPD andschizophrenia are seen. Taken together, this variety of patterns is consistent with a multiplegene model in which several deficits produce schizophrenia, fewer deficits produce SPD, andsome protective or modulatory factors ameliorate full development of schizophrenia in SPD.This model originated from the hypothesis that schizophrenia results from the cumulativeimpact of multiple common small-effect, genetic variants, interacting with environmentalexposures to exceed a biological threshold (Gottesman 1982).

In the temporal lobe, patients with schizophrenia show reduced volume in both left hemisphereBA22 and 21, while SPD patients show small reductions in BA22 but full reduction in BA21.Dickey (Dickey et al 1999) found about a 10% decrease (0.03 for relative data) for BA22 inSPD but did not report schizophrenia data; our SPD decrease in the current study was 0.02 forBA22 but 0.08 for BA21. In our earlier study with a much smaller SPD sample (n=13overlapping with current sample), larger decreases were actually seen for SPD than patientswith schizophrenia for both BA22 and 21. Our overall pattern of temporal lobe volumedecreases being less widespread in SPD than schizophrenia patients, in comparison withhealthy controls is consistent with other studies examining these three groups, e.g., (Kawasakiet al 2004; Takahashi et al 2006b). However, our finding of a shared volume reduction in SPDand schizophrenia patients in middle temporal gyrus is inconsistent with a voxel-based studythat reported shared volume reduction in the left superior but not middle temporal gyrus

Hazlett et al. Page 7

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

(Kawasaki et al 2004). Differences in tracing (Dickey and Downhill studies visually tracedonly the mid-portion of the temporal lobe and identified the superior temporal gyrus), Brodmanarea identification methods (we used a stereotaxic method for separating areas 22 and 21,somewhat more analgous to voxel-basedmorphometry) methods of gray-white segmentation(threshold method used here) , and symptom severity may be important. Both the Kawasakiand Takahashi studies used a clinic-based SPD sample taking low-dose antipsychotics whilewe studied an unmedicated community sample suggesting these samples may differ in illnessseverity.

In the prefrontal cortex, the schizophrenia patients showed overall volume loss in gray but notwhite matter while the SPD patients did not differ from normal. This effect was most markedin BA10 where the schizophrenia patients had smaller volume compared with the healthycontrols while SPD patients had greater-than-normal volume (although not significantlymore). This may result from some variation sparing SPD patients from the full developmentof schizophrenia, an adaptive response to symptoms of the schizophrenia spectrum, or anassociated developmental anomaly among other possibilities. Consistent with our findings,Suzuki et al (2005) demonstrated that the prefrontal volumes were largely preserved in SPDin contrast to widespread prefrontal involvement in schizophrenia. It is of interest that in ourprior FDG-PET study (Buchsbaum et al 2002) using a task involving verbal working memoryin a subgroup of subjects from this study, metabolic rates in BA10 were distinctly higher inSPD patients compared with healthy controls while schizophrenia patients were lowest andthis was determined in the same way as in our present study.

In contrast to the prefrontal and temporal cortex findings where the schizophrenia patientsshowed more gray matter volume loss, the SPD patients showed greater differences fromnormal in cingulate gyrus gray matter. SPD patients had reduced gray matter volume primarilyin BA24, 31, and 23 compared to normal while schizophrenia patients showed a reduction inonly BA31. However, because SPD patients showed significantly greater white matter volumein these same Brodmann areas, the net volume loss in these areas was greater in schizophreniathan SPD. In other words, averaged across all the cingulate BAs, both the SPD andschizophrenia patients had reduced gray matter volume, but the SPD patients had greater-than-normal white matter volume. In a separate sample of chronic patients with schizophrenia, wealso observed the largest gray matter reduction in BA24 and 31 (Mitelman et al 2005b) andothers have also found posterior cingulate volume reduction, (Zhou et al 2005) consistent withthe current results. We previously reported no normal-SPD group differences (Haznedar et al1997) in the cingulate in a subgroup (n=12) of the SPD patients from the current study whichsuggests that large sample sizes are important for detecting subtle group differences. We havediscussed elsewhere in detail (Mitelman et al 2005b) that abnormalities in the posteriorcingulate and BA31 may involve thought disorder and verbal memory. Social anhedonia,important in schizophrenia, is also prominent in SPD patients (Horan et al 2007). A factoranalytic study of the Beck and FDG-PET linked BA31 with anhedonia in unipolar patients(Dunn et al 2002).

The schizophrenia-spectrum fronto-temporal volume abnormalities we observed were relatedto symptom severity. In patients with schizophrenia, negative symptom severity of the illnessas assessed with the BPRS was associated with reduced frontopolar (BA8,9,10) and temporallobe gray matter volume and increased white matter. Among the SPD patients, smaller BA24gray matter volume was associated with greater interpersonal impairment, while smaller STGwhite matter volume was associated with greater cognitive impairment. Previous MRI workreported smaller STG volume was associated with more positive symptoms in schizophreniabut that no significant correlations emerged among the SPD patients (Takahashi et al 2006a).Other work indicates prefrontal and temporal gray matter volume is unrelated to various clinicalsymptoms in schizophrenia while reduced white matter volume in these regions is associated

Hazlett et al. Page 8

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

with negative symptoms (Sanfilipo et al 2000). Differences in patient characteristics mayexplain these differing findings.

This study has a large size with attendant power to detect small differences, an important aspectwhen comparing SPD and normal groups. However, due to the range of diagnoses, the samesymptom severity estimation scales were not available on both SPD patients andschizophrenics. Family history data would have been potentially informative, but was notcollected in a formal structured genetic interview, and so was not included in the analyses. Pasttreatment with neuroleptics may have had some morphological effect. All of the patients inour study were off medication at the time of their MRI scan. While 77% of the SPD patientshad never previously been medicated, 51% of the schizophrenia patients met this criterion.Thus, chronic effects of medication could have been more pronounced in the schizophreniagroup, although the proportion difference is not large. Smaller middle temporal gyrus graymatter volumes in first-episode patients with schizophrenia but not affective psychosis (Kurokiet al 2006) suggest that our finding of a reduction in this same region in both SPD andschizophrenia is not due to prior medication treatment, instead it is a schizophrenia-spectrumspecific abnormality. Future work comparing never-medicated and previously-medicatedschizophrenia-spectrum patients is needed to fully address the issue of medication effects.Recently, a lack of correlation between duration of untreated psychosis and cingulate or frontalsubregion volume was found (Takahashi et al 2007) but the left superior planum temporalevolume was negatively correlated. Hospitalization is presumably more common in theschizophrenia group, so the effects of the inpatient environment on cortical size cannot be ruledout.

Our data analysis tends to reveal gray matter deficits associated with white matter increases.Since each Brodmann area is expressed as relative to whole brain, widespread mm3 decreasesin gray matter might be reflected in relative white matter increases and since we found graymatter decrease in schizophrenia across all four lobes when mm3 data was analyzed, this mustcontribute to the relative white matter increase. However, the white matter increase in patientswas also widespread when absolute mm3 data was analyzed. Thus there are both global tissuefindings as well as regional ones: both BA8 and BA10 break the gray-down/white-up rule. Adetailed analysis with adjustment of regional volumes for brain size estimated from body sizemay help to address this question.

In conclusion, our findings support the concept that SPD is in the schizophrenia spectrum andthe frontal and temporal volume decreases are generally midway between normal andschizophrenia values. Our results suggest that increased volume in prefrontal cortex (BA10)and sparing of volume loss in temporal cortex (BA22 and BA20) may be a protective factor inSPD which reduces vulnerability to psychosis.

Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.

AcknowledgmentThis work was supported in part by an Independent Investigator Award from NARSAD (Dr. Hazlett), NIMH grants(Dr. Hazlett: MH073911; Dr. Buchsbaum: MH40071, MH56489, and MH60023; Dr. Siever: MH56606), a VA MeritAward (Dr. Siever), a grant from the National Center for Research Resources (M01-RR00071) awarded to the GeneralClinical Research Center, Mount Sinai School of Medicine, and a MIRECC VISN3 award.

Hazlett et al. Page 9

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

ReferencesAndreasen N, Flaum M, Arndt S. The Comprehensive Assessment of Symptoms and History (CASH):

An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992;49:615–623.[PubMed: 1637251]

Bergman AJ, Harvey PD, Mitropoulou V, Aronson A, Marder D, Silverman J, et al. The factor structureof schizotypal symptoms in a clinical population. Schizophr Bull 1996;22:501–509. [PubMed:8873300]

Buchsbaum M, Yang S, Hazlett E, Siegel B, Germans M, Haznedar M, et al. Ventricular volume andasymmetry in schizotypal personality disorder and schizophrenia assessed with magnetic resonanceimaging. Schizophr Res 1997;27:45–53. [PubMed: 9373894]

Buchsbaum MS, Nenadic I, Hazlett EA, Spiegel-Cohen J, Fleischman MB, Akhavan A, et al. Differentialmetabolic rates in prefrontal and temporal Brodmann areas in schizophrenia and schizotypalpersonality disorder. Schizophr Res 2002;54:141–150. [PubMed: 11853988]

Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings inschizophrenia: a meta-analysis. Psychiatry Res 2003;122:69–87. [PubMed: 12714172]

Dickey CC, McCarley RW, Shenton ME. The brain in schizotypal personality disorder: a review ofstructural MRI and CT findings. Harv Rev Psychiatry 2000a;10:1–15. [PubMed: 11751641]

Dickey CC, McCarley RW, Voglmaier MM, Frumin M, Niznikiewicz MA, Hirayasu Y, et al. Smallerleft Heschl's gyrus volume in patients with schizotypal personality disorder. The American journal ofpsychiatry 2002b;159:1521–1527. [PubMed: 12202272]

Dickey CC, McCarley RW, Voglmaier MM, Niznikiewicz MA, Seidman LJ, Hirayasu Y, et al.Schizotypal personality disorder and MRI abnormalities of temporal lobe gray matter. Biol Psychiatry1999;45:1393–1402. [PubMed: 10356620]

Dickey CC, McCarley RW, Xu ML, Seidman LJ, Voglmaier MM, Niznikiewicz MA, et al. MRIabnormalities of the hippocampus and cavum septi pellucidi in females with schizotypal personalitydisorder. Schizophr Res 2007;89:49–58. [PubMed: 17027236]

Dickey CC, Shenton ME, Hirayasu Y, Fischer I, Voglmaier MM, Niznikiewicz MA, et al. Large CSFvolume not attributable to ventricular volume in schizotypal personality disorder. Am J Psychiatry2000;157:48–54. [PubMed: 10618012]

Diwadkar VA, Montrose DM, Dworakowski D, Sweeney JA, Keshavan MS. Genetically predisposedoffspring with schizotypal features: an ultra high-risk group for schizophrenia? Progress in neuro-psychopharmacology & biological psychiatry 2006;30:230–238. [PubMed: 16318899]

Downhill JE, Buchsbaum MS, Hazlett EA, Barth S, Lees Roitman S, Nunn M, et al. Temporal lobevolume determined by magnetic resonance imaging in schizotypal personality disorder andschizophrenia. Schizophr Res 2001;48:187–199. [PubMed: 11295372]

Dunn RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, et al. Principal componentsof the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolardepression. Biol Psychiatry 2002;51:387–399. [PubMed: 11904133]

Gottesman, I.; Shields, J.; Hanson, DR. Schizophrenia, the epigenetic puzzle. New York: CambridgeUniversity Press; 1982.

Gur RE, Turetsky BI, Cowell PE, Finkelman C, Maany V, Grossman RI, et al. Temporolimbic volumereductions in schizophrenia. Arch Gen Psychiatry 2000;57:769–775. [PubMed: 10920465]

Hazlett EA, Buchsbaum MS, Haznedar MM, Singer MB, Schnur DB, Jimenez EA, et al. Prefrontal cortexglucose metabolism and startle eyeblink modification abnormalities in unmedicated schizophreniapatients. Psychophysiology 1998;35:186–198. [PubMed: 9529945]

Haznedar MM, Buchsbaum MS, Hazlett EA, Shihabuddin L, New A, Siever LJ. Cingulate gyrus volumeand metabolism in the schizophrenia spectrum. Schizophr Res 2004;71:249–262. [PubMed:15474896]

Haznedar MM, Buchsbaum MS, Metzger M, Solimando A, Spiegel-Cohen J, Hollander E. Anteriorcingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry1997;154:1047–1050. [PubMed: 9247387]

Hazlett et al. Page 10

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Hirayasu Y, McCarley RW, Salisbury DF, Tanaka S, Kwon JS, Frumin M, et al. Planum temporale andHeschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episodepatients. Arch Gen Psychiatry 2000;57:692–699. [PubMed: 10891040]

Horan WP, Brown SA, Blanchard JJ. Social anhedonia and schizotypy: the contribution of individualdifferences in affective traits, stress, and coping. Psychiatry Res 2007;149:147–156. [PubMed:17109970]

Kawasaki Y, Suzuki M, Nohara S, Hagino H, Takahashi T, Matsui M, et al. Structural brain differencesin patients with schizophrenia and schizotypal disorder demonstrated by voxel-based morphometry.European archives of psychiatry and clinical neuroscience 2004;254:406–414. [PubMed: 15538599]

Koo MS, Dickey CC, Park HJ, Kubicki M, Ji NY, Bouix S, et al. Smaller neocortical gray matter andlarger sulcal cerebrospinal fluid volumes in neuroleptic-naive women with schizotypal personalitydisorder. Arch Gen Psychiatry 2006;63:1090–1100. [PubMed: 17015811]

Kuroki N, Shenton ME, Salisbury DF, Hirayasu Y, Onitsuka T, Ersner-Hershfield H, et al. Middle andinferior temporal gyrus gray matter volume abnormalities in first-episode schizophrenia: an MRIstudy. The American journal of psychiatry 2006;163:2103–2110. [PubMed: 17151161]

Mitelman S, Shihabuddin L, Brickman A, Hazlett E, Buchsbaum MS. MRI assessment of gray and whitematter distribution in Brodmann areas of the cortex in patients with schizophrenia with good andpoor outcomes. Am J Psychiatry 2003;160:2154–2168. [PubMed: 14638586]

Mitelman SA, Buchsbaum MS, Brickman AM, Shihabuddin L. Cortical intercorrelations of frontal areavolumes in schizophrenia. Neuroimage 2005a;27:753–770. [PubMed: 15990338]

Mitelman SA, Shihabuddin L, Brickman AM, Hazlett EA, Buchsbaum MS. Volume of the cingulate andoutcome in schizophrenia. Schizophr Res 2005b;72:91–108. [PubMed: 15560955]

Mitropoulou V, Harvey PD, Maldari LA, Moriarty PJ, New AS, Silverman JM, et al. Neuropsychologicalperformance in schizotypal personality disorder: evidence regarding diagnostic specificity. BiolPsychiatry 2002;52:1175–1182. [PubMed: 12488063]

Opler LA, Kay SR, Rosado V, Lindenmayer J. Positive and negative syndromes in chronic schizophrenicinpatients. Jounal of Nervous and Mental Disease 1984;172:317–325.

Overall J, Gorham D. The Brief Psychiatric Rating Scale. Psychological Reports 1962;10:799–812.Perry R, Oakley A, Perry E. Coronal brain map and dissection guide: Localization of Brodman areas in

coronal sections. 1991Pfohl, B.; Blum, N.; M, Z. Structured Interview for DSM-III-R Personality (SIDP-R). Iowa City:

University of Iowa; 1989.Raine A, Sheard C, Reynolds GP, Lencz T. Prefrontal structural and functional deficits associated with

individual differences in schizotypal personality. Schizophr Res 1992;7:237–247. [PubMed:1390403]

Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A, et al. Volumetric measure of thefrontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch GenPsychiatry 2000;57:471–480. [PubMed: 10807487]

Seidman LJ, Faraone SV, Goldstein JM, Kremen WS, Horton NJ, Makris N, et al. Left hippocampalvolume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometricstudy of nonpsychotic first-degree relatives. Arch Gen Psychiatry 2002;59:839–849. [PubMed:12215084]

Seidman LJ, Pantelis C, Keshavan MS, Faraone SV, Goldstein JM, Horton NJ, et al. A review and newreport of medial temporal lobe dysfunction as a vulnerability indicator for schizophrenia: a magneticresonance imaging morphometric family study of the parahippocampal gyrus. Schizophr Bull2003;29:803–830. [PubMed: 14989416]

Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia.Schizophr Res 2001;49:1–52. [PubMed: 11343862]

Siever L, Kalus O, Keefe R. The boundaries of schizophrenia. Psychiatry Clinics of North America1993;15:217–244.

Siever L, Silverman J, Horvath T, Klar H, Coccaro E, Keefe R, et al. Increased morbid risk forschizophrenia-related disorders in relatives of schizotypal personality disordered patients. Arch GenPsychiatry 1990;47:634–640. [PubMed: 2360857]

Hazlett et al. Page 11

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Siever LJ, Davis KL. The pathophysiology of schizophrenia disorders: perspectives from the spectrum.Am J Psychiatry 2004;161:398–413. [PubMed: 14992962]

Siever LJ, Koenigsberg HW, Harvey P, Mitropoulou V, Laruelle M, Abi-Dargham A, et al. Cognitiveand brain function in schizotypal personality disorder. Schizophr Res 2002;54:157–167. [PubMed:11853990]

Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID).I: History, rationale, and description. Arch Gen Psychiatry 1992;49:624–629. [PubMed: 1637252]

StatSoft, I. Statistica. Vol. 6.0 ed.. Tulsa, OK: 2003. www.statsoft.comSuzuki M, Zhou SY, Takahashi T, Hagino H, Kawasaki Y, Niu L, et al. Differential contributions of

prefrontal and temporolimbic pathology to mechanisms of psychosis. Brain 2005;128:2109–2122.[PubMed: 15930048]

Takahashi T, Suzuki M, Tanino R, Zhou SY, Hagino H, Niu L, et al. Volume reduction of the left planumtemporale gray matter associated with long duration of untreated psychosis in schizophrenia: Apreliminary report. Psychiatry Res 2007;154:209–219. [PubMed: 17321114]

Takahashi T, Suzuki M, Zhou SY, Hagino H, Kawasaki Y, Yamashita I, et al. Lack of normal genderdifferences of the perigenual cingulate gyrus in schizophrenia spectrum disorders. A magneticresonance imaging study. European archives of psychiatry and clinical neuroscience 2004;254:273–280. [PubMed: 15365701]

Takahashi T, Suzuki M, Zhou SY, Tanino R, Hagino H, Kawasaki Y, et al. Morphologic alterations ofthe parcellated superior temporal gyrus in schizophrenia spectrum. Schizophr Res 2006a;83:131–143. [PubMed: 16503399]

Takahashi T, Suzuki M, Zhou SY, Tanino R, Hagino H, Niu L, et al. Temporal lobe gray matter inschizophrenia spectrum: a volumetric MRI study of the fusiform gyrus, parahippocampal gyrus, andmiddle and inferior temporal gyri. Schizophr Res 2006b;87:116–126. [PubMed: 16750349]

Talairach, J.; Tournoux, P. Co-planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme; 1988.Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of

regional brain volumes in schizophrenia. Am J Psychiatry 2000;157:16–25. [PubMed: 10618008]Zhou SY, Suzuki M, Hagino H, Takahashi T, Kawasaki Y, Matsui M, et al. Volumetric analysis of sulci/

gyri-defined in vivo frontal lobe regions in schizophrenia: Precentral gyrus, cingulate gyrus, andprefrontal region. Psychiatry Res 2005;139:127–139. [PubMed: 15967647]

Zhou SY, Suzuki M, Takahashi T, Hagino H, Kawasaki Y, Matsui M, et al. Parietal lobe volume deficitsin schizophrenia spectrum disorders. Schizophr Res 2007;89:35–48. [PubMed: 17064881]

Hazlett et al. Page 12

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 1. Delineation of cortical Brodmann areas. Upper left: Perry brain atlas for slice #5 showingfrontal pole Brodmann areas (e.g., 9, 46, 45…) in raw drawing and with sectors added.Upper right: Coronal brain edges are traced on individual MRI slices and set of sectors appliedby computer algorithm, 20 sectors on the lateral and orbital surface (white numbers) and 10 inthe medial portion (green numbers) for a total of 30. Bottom Left: Perry atlas in three-dimensional perspective within MRI surface. Gray and white matter volume within eachBrodmann area is calculated. Bottom right: Diagram of frontal Brodmann areas as colored stickdiagram: area 10 is magenta, area 9 is blue, area 46 yellow, as example.

Hazlett et al. Page 13

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 2.Differences from normal in cingulate gyrus Brodmann area volumes are shown for theschizophrenia spectrum groups. Compared with healthy controls, the schizophrenia patientsshowed the greatest cingulate volume reduction in BA 24 and SPD patients were intermediate(Group × Brodmann area interaction, (F[8,556]=2.92, p=0.003, Wilks). Y-axis shows 100×(roi volume/total brain volume) patients minus normals.

Hazlett et al. Page 14

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 3.Differences from normal in gray/white matter volume in the cingulate gyrus showedsignificantly decreased gray and increased white matter volume in the schizophrenia-spectrumgroups (Group × Matter type × Brodmann area interaction for the cingulate arch, F[8,556]=3.73, p=.0003, Wilks). *all p< 0.04, Fisher’s LSD). “+” denotes SPD>Sz patients, p=0.002,Fisher’s LSD test.

Hazlett et al. Page 15

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 4.Gray and white matter prefrontal cortex volume differences from normal are shown for theschizophrenia-spectrum groups. The schizophrenia patients showed significantly reduced graymatter volume in prefrontal cortex (averaged across hemisphere and all 9 prefrontal cortexBAs which include BA 8, 9, 10, 11, 12, 47, 44, 45, 46) compared with the healthy controls(*N>Sz, p=0.00001, Fisher’s test) and SPD patients (“+” denotes SPD>Sz, p=0.009, Fisher’sLSD test). Group × Matter type interaction, F[2,281]=4.09, p=0.018).

Hazlett et al. Page 16

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 5.Significant Group × Region × Brodmann area interaction (F[8,556]=7.48, p=0.000001) isshown. *C>Sz patients, p=0.003, Fisher’s LSD test. +SPD>Sz patients, p=0.0001, Fisher’sLSD test. The Group × Region interaction (collapsed across BAs within each of the threeregions: anterior, orbital, and dorsolateral) was also significant, F[4,560]=3.28, p=0.01.

Hazlett et al. Page 17

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 6 (TOP).A significant Group × Brodmann area × Matter type interaction (F[4,560]=5.89, p=0.0001)was observed in the temporal lobe. *significantly different from healthy controls, all p valuesbetween 0.04-0.000001, 1SPD>Sz patients, both p<0.0005, Fisher’s LSD test.

Hazlett et al. Page 18

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 6 (BOTTOM).Group × Brodmann area × Hemisphere interaction, F[4,560]=2.79, p=0.026. *significantlydifferent from healthy controls, all p values<0.04, Fisher’s LSD test. A Group×Brodmann areainteraction (collapsed across gray/white matter; F[4,560]=8.09, p=0.000002) indicated that theschizophrenia patients had smaller superior and middle temporal gyrus volume compared withhealthy controls (p<0.031 and p<0.025, respectively) while SPD patients only had reducedmiddle temporal gyrus volume (p<0.002).

Hazlett et al. Page 19

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Figure 7.Group × Lobe × Matter type interaction, F[6, 558]=4.12, p=0.00047, *p=0.0036, Fisher’s LSDtest.

Hazlett et al. Page 20

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Hazlett et al. Page 21Ta

ble

1D

emog

raph

ic a

nd C

linic

al C

hara

cter

istic

s of S

chiz

ophr

enia

Spe

ctru

m G

roup

s and

Hea

lthy

Con

trols

Cha

ract

eris

ticH

ealth

y C

ontr

ols (

n=14

8)SP

D p

atie

nts (

n=79

)Sz

pat

ient

s (n=

57)

Mea

nSD

Ran

geM

ean

SDR

ange

Mea

nSD

Ran

ge

Age

(yea

rs)

35.6

13.0

17–6

537

.9a

10.1

19–6

234

.8b

14.6

17–6

5

Mal

e/fe

mal

e99

/49

62/1

7 c

42/1

5 d

Psyc

hoac

tive

Med

sN

%N

%N

%

N

ever

med

icat

ed-

-61

77%

2951

%

Pr

evio

usly

med

icat

ed-

-18

*23

%28

49%

Clin

ical

Sym

ptom

s:M

ean

SDR

ange

Mea

nSD

Ran

geM

ean

SDR

ange

BPR

S to

tal s

core

48.5

11.3

26–8

3

Po

sitiv

e sy

mpt

om fa

ctor

21.4

6.4

10–3

7

N

egat

ive

sym

ptom

fact

or8.

53.

23–

14

Tota

l num

ber o

f DSM

-III

-R sy

mpt

oms (

of9

poss

ible

)6.

81.

15–

9

C

ogni

tive

impa

irmen

t fac

tor

1.5

.80–

5

In

terp

erso

nal f

acto

r2.

9.9

1–5

Pa

rano

id fa

ctor

2.4

.91–

5a po

st-h

oc t-

test

for H

C v

s. SP

D g

roup

, t(2

25)=

1.36

, p=0

.17.

b HC

vs.

Sz g

roup

, t(2

03)=

0.38

, p=0

.70;

SPD

vs.

Sz g

roup

, t(1

34)=

1.46

, p=0

.15.

c HC

vs.

SPD

gro

up, t

(225

)=1.

84, p

=0.0

7. N

ote:

AN

OV

As r

epor

ted

in re

sults

sect

ion

wer

e al

so a

naly

zed

with

sex

as a

cov

aria

te a

nd th

ey y

ield

ed sa

me

patte

rn o

f res

ults

in te

rms o

f gro

up in

tera

ctio

ns.

d HC

vs.

Sz g

roup

, t(2

03)=

0.94

, p=0

.35;

SPD

vs S

z gr

oup,

t(13

4)=0

.65,

p=0

.52.

* 15 o

f the

pre

viou

sly

med

icat

ed S

PD p

atie

nts r

ecei

ved

a no

n-ne

urol

eptic

med

icat

ion

and

3 re

ceiv

ed n

euro

lept

ics.

All

SPD

and

schi

zoph

reni

a pa

tient

s wer

e of

f psy

choa

ctiv

e m

edic

atio

ns fo

r a m

inim

umof

two

wee

ks p

rior t

o th

eir M

RI s

can.

Schizophr Res. Author manuscript; available in PMC 2009 April 23.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

Hazlett et al. Page 22

Table 3BPRS Symptom correlates of gray and white matter volume in schizophrenia patients.

Positive Symptoms Negative Symptoms

Matter: Matter:

G W G W

BA 24 ns ns ns ns

BA 8 ns −0.30* −0.32* 0.41**

BA 9 ns ns −0.30* ns

BA 10 ns ns −0.37* ns

BA 22 ns ns −0.47** 0.37*

BA 21 ns ns −0.51** 0.43**

BA 20 ns ns −0.41** 0 .35*

*p<0.05, Pearson correlation

**p<0.0018, Bonferroni corrected for p<0.05.

Schizophr Res. Author manuscript; available in PMC 2009 April 23.